tbuckley/cabot-search huggingface dataset:
P029: Are Reed-Sternberg cells stuck in mitosis by short nucleoplasmic bridges as a consequence of centromeric instability?
Authors: Radhia M’Kacher, Steffen Junker, Bruno Colicchio, Wala Najar, Justyna Mika, Alain Dieterlen, Joanna Polanska, Philippe Voisin, Eric Jeandidier, Patrice Carde
Journal: HemaSphere (2022)

Background: Multinucleated giant tumor cells are frequently observed in lymph nodes of untreated lymphoma patients. Malignant Hodgkin lymphoma (HL) cells i. e. small Hodgkin and large bi- or multinucleated Reed-Sternberg (HRS) cells are characterized by genomic instability and downregulation of numerous key regulators of e.g. cell cycle, spindle apparatus, cytokinesis and cell lineage differentiation. So far, the formation of HRS cells remains obscure. We have demonstrated previously that telomere instability is involved in the proliferation of small cells into large binucleated cells. Here, we have used a collection of HL cell lines to analyze the successive steps involved in the transformation of the mononucleated into the multinucleated RS-like cells. Materials and Methods: Seven HL cell lines and 30 HL lymph nodes were used. Cytokinesis-block micronucleus assay and telomere and centromere staining followed by the M-FISH technique were employed to analyze chromosomal instability. DNA repair pathways were investigated. Results: We demonstrate that telomere dysfunction in HL cell lines is associated with the formation of dicentric chromosomes with both centromeres in close proximity, but also with a high rate of formation of micronuclei. Two morphologically different types of nucleoplasmic bridges (NPBs) were observed: (1) Long NPBs related to telomere dysfunction and chromosome fusions, and (2) short NPBs related to centromere breakpoints with configurations of cells looking like “stuck” together as binucleated cells. Short NPBs and binucleated cells were seen in the cultures of all HL cell lines. However, each HL cell line was characterized by an individual signature of the proportion of long and short NPBs, which correlated with centrosome amplification and formation of stable binucleated cells. Similar mechanisms were identified in HL patient lymph nodes prior to treatment, thus underscoring the biological significance of our findings in cell cultures. Transcriptome analysis confirmed the variations in the DNA repair pathways regarding the rate of large cells among the different HL cell lines. Conclusion: The formation of dicentric chromosomes related to centromere instability, and short NPBs were associated with the emergence of binucleated cells through different mechanisms. Our findings open a novel route to understanding the transition from mononucleated cells to multinucleated cells in HL and in other B-cell lymphomas.
P011: IPS-7 or IPS-3 to identify very-high risk patients in advanced Classical Hodgkin’s Lymphoma: Which score to choose
Authors: Cátia Almeida, Rita Costa E. Sousa, Adriana Roque, Maria Carolina Afonso, Dulcelena Neves, Raquel Guilherme, Lenka Ruzickova, José Pedro Carda, Catarina Geraldes, Marília Gomes
Journal: HemaSphere (2022)

Figure 1: PFS and OS for both IPS-3 and IPS-7 scores Introduction: The survival of patients (pts) with classic Hodgkin Lymphoma (cHL) has been significantly increased due to refinement of therapeutic strategies. International Prognostic Score (IPS-7) is the most used risk stratification tool for patients with advanced-stage cHL but it may have decreased prognostic value in cHL pts treated in the contemporary era. A novel scoring system, IPS-3, comprising three of the seven IPS-7 indicators (age ≥45, stage IV, haemoglobin <105 g/L), was recently proposed to identify high-risk patients but require further validation. Aim: To validate IPS-3 and evaluate its discriminatory power in advanced stages cHL. Methods: Single centre retrospective analysis of adult pts with cHL diagnosed between 1990 and 2017 treated with ABVD, ABVD hybrid protocols or escalated BEACOPP. Advanced stage was defined according to the German Hodgkin Study Group classification system. Stratified models for IPS-3 and IPS-7 were compared using Akaike’s information criteria (AIC) and Harrell’s concordance index (C-index). Results: We included 227 pts, with similar gender proportion; median age was 32.3 (18–80). Nodular sclerosis was the most common histologic subtype (n=176 pts; 77.5%); 90 pts (39.6%) presented stage IV; 13 pts (5.7%) had IPS-3 high risk, 12 pts (5.3%) IPS-7 high risk and 8 pts (3.5%) had both. After a median follow-up of 123 months (m), the median overall survival (OS) was not reached. IPS-7 (HR 2.13 [95%IC 1.49–3.05]; p<0.001) and IPS-3 (HR 3.05 [95%IC 1.98–4.69]; p<0.001) identify different prognosis groups for OS, with IPS-3 (AIC 633; C-index 0.6547) providing best fit for data compared with IPS-7 (AIC 643; C-index 0.6403). Median progression free survival (PFS) was 295.6m. IPS-7 (HR 1.43 [95%IC 1.05–1.96]; p=0.025) and IPS-3 (HR 1.72 [95%IC 1.20–2.46]; p=0.003) identified different prognostic groups for PFS, with IPS-3 (AIC 917; C-index 0.5717) providing best fit for data compared with IPS-7 (AIC 921; C-index 0.5570). IPS-3 remained predictive for OS (HR 3.05; p<0.001) and PFS (HR 1.72; p=0.003) after adjustment for treatment protocol and had a good performance discriminating high vs intermediate/low risk for OS and PFS (HR 2.40; p=0.002 and PFS HR 3.03; p=0.001, respectively). Conclusion: IPS-3 had better performance predicting OS and PFS compared with IPS-7, allowing a better segregation of patients with worse prognosis, which suggests its value to identify patients that will benefit more aggressive treatment protocol.
P091: Early analysis of the PRO-Hodgkin study: Clinical investigation of pencil beam scanning proton treatment in Hodgkin lymphoma patients
Authors: Christina Goldkuhl, Alexandru Dasu, Anna Bäck, Gunilla Enblad, Ingrid Glimelius, Annika Hall, Lotta Hansson, Urban Jerlström., Ann-Sofie Johansson, Jenny Kahlmeter-Brandell, Johan Linderoth, Marzia Palma, Hillevi Rylander, Marika Enmark, Daniel Molin
Journal: HemaSphere (2022)

Background: Most stage I-IIA classical Hodgkin lymphoma (cHL) patients are cured with limited chemotherapy followed by radiotherapy (RT), with a risk of late toxicity from RT. The dose to normal tissue can be minimized with proton therapy (PT) due to the finite range in tissue and the rapid dose-drop beyond that. This study reports preliminary results of the PRO-Hodgkin study. Method: The first 19 patients included (median age 31 (19–53)) are analysed. They received 2–4 cycles of ABVD followed by involved-node/site PT to 29.75 Gy (RBE; relative biological effectiveness)/17 fractions for patients with risk factors, and 20 Gy (RBE)/10 fractions for those without risk factors. Planning CT in deep inspiration breath hold was recommended; if not feasible, a 4DCT was performed to ensure motion amplitudes within 5 mm. Patients were typically treated by pencil beam scanning with two anterior oblique fields, sometimes with a complementary posterior field. All treatment plans were robustly optimized. Results: All patients were in complete remission at end of therapy. Acute toxicity was generally limited and similar to photon treatment, except slightly more skin reaction, which occurred in all patients (1 grade 3, 1 grade 2 and 17 grade 1). Surprisingly 4 patients (age 26–45), previously healthy and non-smokers, presented with skin hyperesthesia radiating from the neck or the scapula/chest wall area towards the axilla and upper arm, starting weeks or a few months after RT. The symptoms mostly resolved within a month, but one patient had symptoms gradually improving for 4 months. None of the patients had skin rash during symptoms and none had motor affection. Analysis of the dose plans showed that the brachial nerve plexus was frequently located in or close to the target, and often had a modest overdosage (max 5% over the prescribed dose). Thoracic nerve roots and the spinal cord were usually located in the dose drop-off. Even assuming slightly higher RBE towards the end of the proton range, the dose to spinal cord/peripheral nerves was well within tolerance. Conclusion: PT was generally well tolerated, except for an unexpected, transient neurological toxicity in 4 out of 19 patients. This could not be explained by an overdosage, and the potential mechanism has not yet been identified. Radiation- induced inflammation and cytokine release could be a possible cause. Further analyses are warranted and neurological toxicity will be reported for future patients.
P017: The role of baseline bulk and dissemination measures as predictors of progression in advanced Hodgkin lymphoma
Authors: Michal Taszner, Grzegorz Romanowicz, Wanda Knopińska-Posłuszny, Janusz Hałka, Edyta Subocz, Bogdan Małkowski, Jan Maciej Zaucha
Journal: HemaSphere (2022)

Figure 1: Probability of progression-free survival by baseline MTV (A) and Dmax (B) Introduction: Numerous clinical and FDG-PET/CT-associated models were proposed to predict treatment failure in Hodgkin’s lymphoma (HL). Baseline quantitative FDG-PET metrics are emerging biomarkers showing promising prognostic value. We retrospectively analysed the impact of tumour bulk and dissemination as measured by assessing Metabolic Tumor Volume (MTV) and D max - the distance between the furthest lesions identified by FDG-PET/CT - on the probability of progression in HL patients in clinical stages II to IV. Methods: Baseline FDG-PET/CT data of 117 patients with newly diagnosed HL from the PLRG-11 study was analysed and MTV was assessed by manual segmentation with the volume of interest (VOI) threshold of 41%SUVmax and Dmax was calculated by measuring the diameter between centroids of VOIs with SUVmax above SUVmax of the liver located furthest apart. The Median follow-up was months. The distance was measured in 3-dimensional space using Euclidean geometry. The cut-off values of MTV and Dmax were calculated with the maximally selected rank statistic method. Results: MTV cut-off value for progression-free survival (PFS) prediction was 214 ml with PPV 0,516 and NPV of 0.848 and for Dmax was 10 cm with PPV 0.291 and NPV of 1.0. In the cohort of 69 patients with negative interim PET/CT performed post-second cycle of ABVD PFS event was reported in 0% and 17% patients with Dmax below and above 10 cm, respectively and in 6% and 36% of patients with MTV below and above threshold value of 214 ml, respectively. Conclusion: Bulk and dissemination assessments in baseline PET/CT in Hodgkin lymphoma stage II-IV patients may help identify a population of patients with an especially good prognosis.
P024: Predictive Value of Baseline Metabolic Tumor Volume in Early-Stage Favorable Hodgkin Lymphoma – Data from the Prospective, Multicenter Phase III HD16 Trial
Authors: Lutz Van Heek, Colin Stuka, Helen Kaul, Horst Müller, Jasmin Mettler, Felicitas Hitz, Christian Baues, Michael Fuchs, Peter Borchmann, Andreas Engert, Markus Dietlein, Conrad-Amadeus Voltin, Carsten Kobe
Journal: HemaSphere (2022)

Background: 18F -fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the staging and response assessment of lymphoma patients. Our aim was to explore the predictive relevance of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with early stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD16 trial. Methods: 18F-FDG PET/CT images were available for MTV and TLG analysis in 107 cases from the HD16 trial. We calculated MTV and TLG using three different threshold methods (SUV4.0, SUV41% and SUV140%L), and then performed receiver-operating-characteristic analysis to assess the predictive impact of these parameters in predicting an adequate therapy response with PET negativity after 2 cycles of chemotherapy. Results: All three threshold methods analyzed for MTV and TLG calculation showed a positive correlation with the PET response after 2 cycles chemotherapy. The largest area under the curve (AUC) was observed using the fixed threshold of SUV4.0 for MTV- calculation (AUC 0.69 [95% CI 0.55–0.83]) and for TLG-calculation (AUC 0.69 [0.55–0.82]). The calculations for MTV and TLG with a relative threshold showed a lower AUC: using SUV140%L AUCs of 0.66 [0.53–0.80] for MTV and 0.67 for TLG [0.54–0.81]) were observed, while with SUV41% an AUC of 0.61 [0.45–0.76] for MTV, and an AUC 0.64 [0.49–0.80]) for TLG were seen. Conclusions: MTV and TLG do have a predictive value after two cycles ABVD in early stage Hodgkin lymphoma, particularly when using the fixed threshold of SUV4.0 for MTV and TLG calculation.
P051: Serum procalcitonin levels in newly diagnosed classical Hodgkin Lymphoma (cHL): Correlation with other inflammatory biomarkers
Authors: Alexia Piperidou, Eleftherios Zografos, Theodoros P. Vassilakopoulos, Maria K. Angelopoulou, Georgios Hlias, Vassiliki Pappis, George Boutsikas, Maria Dimou, Kyriaki Petevi, Alexandros Kanellopoulos, Marie-Christine Kyrtsonis, Panayiotis Panayiotidis, Theodoros P. Vassilakopoulos
Journal: HemaSphere (2022)

Introduction: In the recent years procalcitonin (PCT) has emerged as a useful biomarker for the diagnosis of sepsis and bacterial infection. Inflammatory markers are elevated in the majority of patients with cHL, a finding that may cause diagnostic issues. Ongoing infection rarely coexists with HL at the time of diagnosis. PCT levels might be helpful in differentiating bacterial infection from non-bacterial, disease-related inflammation, which are both characterized by elevated CRP levels. Materials and Methods: In order to assess whether and to what extent the underlying chronic inflammatory condition is associated with elevated PCT levels, we collected data on serum PCT levels and other routine inflammation markers in newly diagnosed cHL patients. Values <0.50 ng/mL were considered normal; 0.10–0.50 ng/mL were normal/detectable, while <0.10 ng/mL were normal/undetectable. Serum PCT levels were considered elevated if exceeded the cut-off of 0.50 ng/mL. Results: Among 137 patients diagnosed with cHL between April 2010 and August 2015, 55 had B-symptoms (40%), ESR was ≥50 mm/h in 77/130 (59%) and 116 patients (85%) had elevated CRP; the median CRP was 38.1 mg/L (range;2.97–328.0). The median serum ferritin was 154.10 ng/ml (range;7-6709) and leukocytosis (WBC ≥15x109/L) was recorded in 20 (15%) patients. Serum PCT levels were normal in the vast majority of the patients [normal/undetectable 94/137(68.5%) and detectable 41/137(30%)] with median value <0.10 ng/ml (<0.10–15.90). Only 2 patients had elevated PCT levels (1.5%). Patients who had serum PCT<0.10 ng/ml had lower median CRP [25.75; range(2.97–203.0)] compared to patients with PCT ≥0.10 ng/ml who had median CRP of 92.50 mg/L(range;3.34–328.0; p<0.001). Almost all patients (40/41, 97.6%) with detectable PCT levels had also elevated CRP. Compared to patients with normal/undetectable levels, those with PCT ≥0.10 ng/ml had more frequently advanced disease (83%), B symptoms (73%), ESR≥50 (82%), anemia (81%), hypoalbuminemia (90%), leukocytosis (27%) and higher serum ferritin, haptoglobin and a2-globulin levels. Conclusion: This is the first study showing that the inflammatory condition characterizing cHL is not associated with serum PCT elevations although CRP levels are elevated in 85% of them. Consequently, normal serum PCT levels may rule out the diagnostic possibility of occult infection, thus preventing extensive evaluation, which may further delay in treatment initiation.
P101: Combination of immune checkpoint inhibitors with BeGEV in the treatment of patients with relapsed and refractory classical Hodgkin’s lymphoma.
Authors: Ya.K. Mangasarova, T.N. Moiseeva, L.S. Al-Radi, O.V. Margolin, L.G. Gorenkova, E.S. Nesterova, M.O. Bagova, E.A. Fastova, R.R. Abdurashidova, Z.T. Sarakaeva, Elena Dorokhina, S.K. Kravchenko, A.U. Magomedova, E.E. Zvonkov
Journal: HemaSphere (2022)

Introduction: Given the wide range of effectiveness of various high-dose chemotherapy regimens in patients with r/r HL, the lack of a unified treatment protocol, an active search is currently underway for the place and sequence of using new classes of drugs and their combination with classical chemotherapy. Objective: Analysis of treatment effectiveness and toxicity in patients with r/r cHL according to the BeGEV regimen in combination with nivolumab at a fixed dose of 40 mg. Materials and Methods: Since 2019 we conducted a pilot multicenter prospective study for r/r cHL patients - candidates for auto-HSCT. By 2022, 35 patients were included. The treatment protocol consisted of 2 cycles of chemotherapy according to Nivo40-BeGEV scheme (vinorelbine 20 mg/m2 on day 1, dexamethasone 20 mg/m2 on days 1–5, gemcitabine 800 mg/m2 on days 1 and 4, bendamustine 90 mg/m2 on days days 2 and 3, nivolumab 40 mg IV on day 0) with further assessment of response by PET/CT. When a complete metabolic response was achieved, an additional one course of chemotherapy Nivo40-BeGEV was performed and then auto-HSCT (BeEAM) was held. If a partial remission after 2 cycles of chemotherapy and a complete remission after 4 cycles has not been achieved, the patient was excluded from the treatment protocol. Results: Treatment according to the Nivo40-BeGEV regimen was completed in 35 patients. All patients achieved complete remission, most after 2 cycles - 34/35 (97.1%). Effective mobilization of HSC and auto-HSCT was performed in 30/34 (85.7%) patients. Complete remission of r/r cHL is maintained in 33/35 (94.2%) patients with a follow-up of 1–34 months, and 2/35 (5.7%) patients had an early relapse of the disease. EFS and OS were 95% and 100%, respectively, with a median follow-up of 13 months. Infectious, immune complications grade III-IV were not detected. Hematological toxicity grade III-IV has been observed in 3/35 (8.5%) patients. Conclusion: The combination of nivolumab at a fixed dose of 40 mg with chemotherapy BeGEV has demonstrated high efficacy and the absence of severe adverse eventes in patients with r/r cHL.
P049: Reduced features of T-cell activation before and during anti-PD-1 treatment in classical Hodgkin lymphoma
Authors: Nicole Seifert, Sarah Reinke, Johanna Grund, Berit Müller-Meinhard, Andreas Engert, Paul J. Bröckelmann, Wolfram Klapper, Michael Altenbuchinger
Journal: HemaSphere (2022)

Figure 1: Unbiased Clonality by primary and follow-up biopsies of different cohorts. Stars denote a statistically significant difference in Unbiased Clonalities of two cohorts (Welch’s Two Sample t-test, ** p < 0.01, *** p<0.001) Hodgkin- and Reed-Sternberg cells (HRSC) proliferate in a presumably highly immunogenic tumor microenvironment (TME) containing abundant CD4+ and CD8+ T-cells. Even though anti-PD-1 directed treatment is clinically well established, the mechanism of action in classical Hodgkin lymphoma (cHL) is still incompletely understood. To elucidate features of a T-cell mediated immune response in cHL, we studied HRSC immunogenicity defined by human leukocyte antigen (HLA) expression, associated T-cell expansion, and TME composition. We analyzed T-cell Receptor (TCR) repertoires, bulk gene expression levels and whole-slide images of treatment-naïve cHL patients before (n=90) and on anti-PD-1 therapy (n=4) in the NIVAHL phase II trial (Bröckelmann et al. JAMA Oncol 2020). In independent cohorts of breast cancer (n=6), benign lymph nodes (n=8) and cHL treated with chemotherapy (n=18), a biopsy both at primary diagnosis and relapse was available. To describe the proliferative activity of T-cells in the TME, we used three measures: debiased Simpson’s clonality (Unbiased Clonality; UC), Percentage of Singletons (PoS), and clonal expansion. We identified significantly lower UC and higher PoS in pre-treatment cHL compared to breast cancer specimens. Moreover, cHL showed less expansion of TCR clones in follow-up biopsies than breast cancer. A pair-wise comparison of pre- and on-anti-PD-1 treatment cHL specimens did not show a significant difference in UC or PoS. However, an analysis of primary versus relapse (after chemotherapy) biopsies of cHL showed a trend to increased UC in relapse specimens. Next, we analyzed bulk gene expression and TCR repertoires with respect to HLA I and II status on HRSC. HLA status was not associated with UC or PoS. However, we observed a significant enrichment of CD8+ T-cells and up-regulation of cytotoxicity genes in the bulk TME of HLA I+ HRSC. This trend seems to persist for both CD8+ T-cells close and more distant to HRSC (see Müller-Meinhard et al., ISHL12 submission). In summary, we did not observe features of a T-cell activation (UC, PoS, clonal expansion) in cHL pre- and on-anti-PD-1 treatment biopsies. Our findings suggest a cHL TME that contains a polyclonal mass of T-cells not activated early during anti-PD-1 treatment. However, our analyses cannot exclude an increased clonality in cHL at later timepoints or in relapse biopsies after conventional chemotherapy.
P072: Impact of Ageing on the Survivorship Experiences of Patients with Hodgkin Lymphoma
Authors: Cherie Bates, Funmi Bamigbola, Lorna Warwick
Journal: HemaSphere (2022)

Table 1: shows various aspects of the survivorship experience of patients with HL including the prevalence of psychosocial issues, the impact of their symptoms and treatment side effects and the changes experienced transitioning into survivorship. Background: Lymphoma Coalition (LC) used its 2022 Global Patient Survey (GPS) on Lymphomas and CLL to examine the impact of ageing on the survivorship experiences of patients with Hodgkin lymphoma (HL) who were in remission. Methods: 1,045 respondents had HL and 447 of them identified as being in remission and were included in this analysis. These patients were grouped into two age groups for analysis, based on their current age at survey time: 18-39yrs (n=248) and 40yrs+ (n=199). Demographics of the two age groups were examined, and descriptive analyses for all questions relating to their survivorship experience were performed in IBM SPSS v27. Results: Patients were asked which psychosocial issues they had experienced over the last 12 months because of their lymphoma. The older age group (40+) reported the lowest prevalence of every psychosocial issue listed (Table 1). The older age group (40+) also reported the highest prevalence of experiencing no psychosocial issues (‘none’) (19%). Fear of relapse of HL was the most prevalent psychosocial issue in both age groups (18–39- 80% and 40+- 63%) (Table 1). Patients who reported experiencing symptoms of HL and/or side effects of treatment were asked how these symptoms and/or side effects impacted their life, including everyday activities, employment, social life, and relationships (Table 1). Both age groups differed significantly in how they experienced these impacts with the lowest prevalence for each of these impact categories being observed in the older age group (40+) (Table 1). When asked about their transition from cancer care into survivorship, patients in both groups had similar experiences in the areas of follow-up visits, knowledge of whom to contact about health issues, and feeling supported, but differed in their knowledge regarding their personal post-treatment care plan (Table 1). About half of patients in both groups felt as supported in their survivorship experience as when they were receiving active care. Conclusions/Summary: Compared to the older survivors, younger survivors with HL are disproportionately affected by psychosocial issues and are more impacted by the effect of their symptoms and side effects. Addressing the psychosocial and support needs of all HL survivors should be a key part of their care and it is important for health care providers to know that younger patients may require additional attention and support.